The overall objective of the proposed work is to delineate the pharmacogenetics of indolealkylamine (IAA) metabolism and drug-drug interactions. IAA xenobiotics represent a major class of psychoactive drugs that have seen widespread abuse. Currently, these substances are easily synthesized in clandestine laboratories and sold via the internet. Overdosing or concomitant use of IAA xenobiotics may cause severe or even fatal "serotonin toxicity". The pharmacological and toxicological effects of IAA drugs exhibit broad interindividual variations, but the underlying mechanisms remain elusive. Variation of IAA metabolism and disposition is likely one reason. Recently, we have shown that O-demethylation is a significant metabolic pathway for five IAA drugs. Cytochrome P450 2D6 (CYP2D6), which is known for its genetic polymorphism, mediates this reaction. We therefore hypothesize that CYP2D6 polymorphism may be an important determinant of the inter-individual responses toward IAA, and that this phenomenon will produce considerable variability in IAA metabolism, pharmacokinetics and pharmacodynamics, as well as the severity of IAA drug-drug interactions. In Aim #1, kinetic studies with genotyped hepatocytes are proposed to assess the variability of IAA intrinsic clearance and metabolite production in relation to CYP2D6 genotypes or phenotypes. Aim #2 will test the hypothesis that variations of IAA drug effects are related to CYP2D6 status. We propose to use the CYP2D6-trangenic mouse model for these studies, which will allow us to assess directly the impact of CYP2D6 on IAA metabolism, pharmacokinetics, and dynamics at the systemic level. Aim #3 will investigate IAA drug-drug interactions, which is reasoned to occur at both the pharmacodynamic and pharmacokinetic levels. We will employ the same mouse models to characterize their association with CYP2D6 status and IAA dose combinations. We will use kinetic, biochemical, physiological, and behavioral measurements as endpoints to assess IAA pharmacogenetics and complex drug-drug interactions. Based upon our intriguing preliminary data, we believe that the proposed work will advance the understanding of IAA pharmacology and toxicology. Characterization of the genetic factors that control IAA kinetics and drug effects on animal behavior, brain neurotransmitters, and body temperature is anticipated to provide important basic information and insights concerning IAA metabolic and toxicological determinants.